Anthracyclines are anticancer agents with a broad spectrum of activity in oncological practice. However, the use of anthracyclines is limited by the cardiotoxicity they may induce . Following the administration of anthracyclines in the setting of adjuvant therapy for breast cancer, trastuzumab (Herceptin ^® ), a humanized monoclonal antibody against the human epidermal growth factor receptor 2 (HER 2) protein, is effective in patients that overexpress this receptor . The addition of trastuzumab therapy to sequential anthracycline and taxane adjuvant treatment reduced the risk of breast cancer recurrence by nearly one-half, and the risk of death by one-third . However, while preclinical studies did not reveal cardiotoxicity, later clinical studies showed that treatment with trastuzumab led to an unexpected incidence of cardiac side-effects . The most frequent effect was reduced systolic ventricular function, asymptomatic or associated with heart failure.

In patients treated with cardiotoxic chemotherapies, the presence of cardiovascular risk factors and previous cardiac disease has been strongly correlated to the onset of cardiotoxicity. Among these factors, age is one of the major predictors of cardiac events after anthracycline treatment, increasing the risk of cardiotoxicity 2.25-fold in patients aged >65 years . Diabetes and dyslipidaemia have also been shown to be associated with a higher incidence of anthracycline cardiomyopathy .

Being overweight or obese is a complex health problem that affects a growing number of populations, and several factors increase the incidence of cancer in overweight and obese individuals . Obesity has been associated with poor outcome in patients with breast cancer treated with anthracycline-based chemotherapy, affecting both overall survival and disease-free survival, and is an important prognostic factor, independent of treatment dose . Conversely, other studies have indicated that body mass index (BMI) has no effect on disease-free survival, but only has a significant negative impact on overall survival , suggesting that obese women with breast cancer have poorer overall survival, possibly because of a higher risk of non-cancer-related causes of death. This may be explained, in part, by the potentially higher likelihood of cardiac adverse events in obese patients treated with anthracyclines or trastuzumab. Thus, obesity may increase cancer mortality indirectly, through the cardiovascular system .

Both total obesity, measured by BMI, and central obesity, measured as waist circumference or waist-to-hip ratio, are associated with an increased risk of cardiovascular death . Although it has been reported for many years that patients with metabolic syndrome have a higher risk of cardiovascular pathologies, their susceptibility to developing chemotherapy-induced cardiac disease was not well documented until recently. In fact, a study has shown that rats fed a high-lipid diet are more sensitive to the cardiotoxic effects of anthracyclines. We recently demonstrated in an “overweight” rodent model (induced by post-natal overfeeding) that these mice are prone to develop cardiac alterations following the administration of anthracyclines and trastuzumab . Consequently, we aimed to transpose our results to humans. We performed a random-effects and a network meta-analysis that included 15 studies and 8745 patients with localized and metastatic breast cancer, treated with adjuvant or neoadjuvant anthracyclines and/or trastuzumab . Being overweight or obese was significantly associated with a greater risk of developing cardiotoxicity after anthracyclines and sequential anthracyclines plus a trastuzumab regimen in patients with breast cancer. The pooled odds ratio for cardiotoxicity was 1.38 (95% confidence interval [CI] 1.06–1.80; I ² = 43%; n = 8745) for being overweight or obese (BMI > 25 kg/m ² ), 1.47 (95% CI 0.95–2.28; I ² = 47%; n = 2615) for being obese, and 1.15 (95% CI 0.83–1.58; I ² = 27%; n = 2708) for being overweight. Associations were independent of the study design, year of publication, drug regimen (anthracyclines alone versus sequential anthracyclines plus trastuzumab) and definitions of cardiotoxicity and overweight/obese. However, we could not separate the contributions of obesity-related cardiovascular risk factors, such as diabetes and hypertension, from that of obesity itself in this largely unadjusted analysis.